Cystatin F Is a Glycosylated Human Low Molecular Weight Cysteine Proteinase Inhibitor

Ni, Jian; Fernandez, Marcia Alvarez; Danielsson, Lena; Chillakuru, Rajeev A.; Zhang, Junli; Grubb, Anders; Su, Jeffrey; Gentz, Reiner; Abrahamson, Magnus

doi:10.1074/jbc.273.38.24797

Cited by 144 publications

(146 citation statements)

References 52 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…Each family of the cystatin superfamily consists of multiple members ; cystatin family 2 contains the most members, including cystatins C, S, SN, SA [1] and, more recently, cystatins D, E\M and F [7][8][9][10]. The tissue expression of the cystatins varies : some cystatins such as cystatin D exhibit a more restricted tissue distribution [7], whereas others such as cystatin C are more Abbreviations used : Cres gene, cystatin-related epididymal spermatogenic gene ; 5h RACE, rapid amplification of 5h cDNA ends ; RT-PCR, reverse transcriptase-mediated PCR.…”

Section: Introductionmentioning

confidence: 99%

Structure, alternative splicing and chromosomal localization of the cystatin-related epididymal spermatogenic gene

Hsia

Sutton

1999

Biochemical Journal

View full text Add to dashboard Cite

The cystatin superfamily of cysteine protease inhibitors consists of three major families, including the stefins, cystatins and kininogens. However, the recent identification of several genes that possess sequence similarity with the cystatins but have different gene or protein structures indicates that several new cystatin families or subgroups of families might exist. We previously identified the cystatin-related epididymal spermatogenic (Cres) gene, which is related to the family 2 cystatins but exhibits highly tissue-specific expression in the reproductive tract. In the studies presented here, an analysis of gene structure as well as chromosomal mapping studies suggest that the Cres gene might represent a new subgroup within the family 2 cystatins. Although the Cres gene possesses an additional exon encoding 5ʹ untranslated sequences, its coding exons are similar in size to the three coding exons of the cystatin family 2 genes, and the Cres exon/intron splice junctions occur in identical locations as in the cystatin C gene. Furthermore, chromosomal mapping studies show that the Cres gene co-segregates with the cystatin C gene on mouse chromosome 2. Similar to the cystatin family 2 proteins, the Cres protein possesses the type A and B disulphide loops that are necessary for cystatin folding. Interestingly, Cres protein also possesses half of a type C disulphide loop. Although probably related to the cystatin genes, the Cres gene is distinct in that its promoter contains consensus motifs typical of regulated genes. Finally, reverse transcriptase-mediated PCR studies and the identification of new Cres cDNA clones indicate that the Cres mRNA is alternatively spliced, resulting in two Cres

show abstract

Section: Introductionmentioning

confidence: 99%

Structure, alternative splicing and chromosomal localization of the cystatin-related epididymal spermatogenic gene

Hsia

Sutton

1999

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…The inhibitor shares Ͻ35% sequence identity with other type II cystatins and possesses a unique extension of ϳ6 amino acids at its N terminus. Compared with other cystatins, the protein exhibits a distinct specificity profile, binding tightly to cathepsins F, K, L, and V, less tightly to cathepsins S and H, and not inhibiting cathepsins B, C, or X (20,22). Although cystatin F can inhibit AEP, its affinity is reduced compared with other AEP binding cystatins (11).…”

mentioning

confidence: 98%

“…Although cystatin F can inhibit AEP, its affinity is reduced compared with other AEP binding cystatins (11). The expression of cystatin F is limited to hematopoietic cells, with the highest expression levels being observed in monocytes, dendritic cells, and certain types of T-cells (19,20). Furthermore, it has been shown that cystatin F mRNA becomes up-regulated during dendritic cell maturation (23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural Basis of Reduction-dependent Activation of Human Cystatin F

Schüttelkopf

Hamilton

Watts

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cystatins are important natural cysteine protease inhibitors targeting primarily papain-like cysteine proteases, including cathepsins and parasitic proteases like cruzipain, but also mammalian asparaginyl endopeptidase. Mammalian cystatin F, which is expressed almost exclusively in hematopoietic cells and accumulates in lysosome-like organelles, has been implicated in the regulation of antigen presentation and other immune processes. It is an unusual cystatin superfamily member with a redox-regulated activation mechanism and a restricted specificity profile. We describe the 2.1 Å crystal structure of human cystatin F in its dimeric "off" state. The two monomers interact in a fashion not seen before for cystatins or cystatin-like proteins that is crucially dependent on an unusual intermolecular disulfide bridge, suggesting how reduction leads to monomer formation and activation. Strikingly, core sugars for one of the two N-linked glycosylation sites of cystatin F are well ordered, and their conformation and interactions with the protein indicate that this unique feature of cystatin F may modulate its inhibitory properties, in particular its reduced affinity toward asparaginyl endopeptidase compared with other cystatins.

show abstract

“…Cystatin F is expressed primarily in cells of the immune system, such as dendritic cells, T cells and NK cells (72)(73)(74). While other type II cystatins are mainly secreted, the intracellular levels of cystatin F are unusually high, implying an important intracellular role (75).…”

Section: Cystatins and The Immune Responsementioning

confidence: 99%

Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

et al. 2017

View full text Add to dashboard Cite

Cystatins comprise a superfamily of evolutionarily related proteins, present in all living organisms, from protozoa to mammals. They act as inhibitors of cysteine peptidases although they can also function independently of their inhibitory function. Cysteine cathepsins are implicated in various physiological and pathological processes. In the immune response they are involved in antigen processing and presentation, the cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), migration and adhesion of immune cells, cytokine and growth factor regulation and toll-like receptor signalling. Cystatins are probably involved in the regulation of all these processes; importantly, cystatin F has a crucial role in the regulation of immune cell cytotoxicity. NK cells and CTLs exploit the granzyme/perforinAmong those peptidases involved in immune processes, many studies have been focused on a group of endosomal/lysosomal cysteine peptidases, the cysteine cathepsins, whose involvement in antigen processing and presentation, cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), migration and adhesion of immune cells, cytokine and growth factor regulation and toll like receptor (TLR) signalling have been demonstrated (3,4). In addition to cathepsins, another lysosomal cysteine peptidase, legumain or asparaginyl endopeptidase, has also been associated with the immune response, most notably with antigen presentation and TLR signalling (4, 5). The activities of cysteine cathepsins and legumain are regulated on different levels. Their expression, for example, is regulated at transcriptional or translational levels. They are synthesised as inactive precursors, activated only at the site of action, and compartmentalised into lysosomes or other organelles. Their activity can be regulated by oxidation of the active site cysteine or by endogenous protein inhibitors (6), the latter being presented in more detail. CYSTEINE CATHEPSINS AND LEGUMAIN AS REGULATORS OF THE IMMUNE RESPONSEIn humans, cysteine cathepsins comprise a group of 11 lysosomal peptidases (cathepsins B, C, F, H, K, L, O, S, V, X and W). They are members of the papain family, classified as clan CA (7). The expression pattern, levels, localization and specificities of cysteine cathepsins differ, contributing to their various physiological roles. Cathepsins B, H, L and C are expressed ubiquitously in cells and tissues, while expression of others is restricted to specific cell types. They are endopeptidases, with the exception of cathepsins B, C, H and X. Cathepsins B and X are carboxypeptidases, cleaving substrates at the C-terminal end, while cathepsins B and H are aminopeptidases, cleaving substrates at the N-terminal end. Interestingly, in addition to exopeptidase activity, cathepsins B and H also exhibit endopeptidase activity (7,8). Cathepsin B can act as an endo-or exopeptidase due to the position of the structural element, termed the occluding loop, while in cathepsin H the type of activity is determined by a minicha...

show abstract

Cystatin F Is a Glycosylated Human Low Molecular Weight Cysteine Proteinase Inhibitor

Cited by 144 publications

References 52 publications

Structure, alternative splicing and chromosomal localization of the cystatin-related epididymal spermatogenic gene

Structure, alternative splicing and chromosomal localization of the cystatin-related epididymal spermatogenic gene

Structural Basis of Reduction-dependent Activation of Human Cystatin F

Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

Contact Info

Product

Resources

About